tbuckley/cabot-search huggingface dataset:
Abstract SY30-03: Composing each patient’s equation: Unraveling brain tumor complexity by integrating multi-regional image-localized biopsies
Authors: Kristin R. Swanson
Journal: Cancer Research (2023)

Abstract Glioblastoma is a uniquely challenging and aggressive cancer that is practically considered uniformly fatal. This aggressiveness is driven by heterogeneity between and within patients and the diffuse invasion of tumor cells deep into the normal appearing brain tissue surrounding the frank tumor abnormality. Mathematical neuro-oncology (MNO) is a burgeoning field that seeks to bring together individual patient data (like patient imaging, tissue biopsies etc) to tune mathematical models that accurately predict and quantify response to treatments for each patient. These mathematical models use both mechanistic “weather forecasting” methods and artificial intelligence pattern recognition methods. Ultimately, these models form the basis of modern "precision medicine" approaches to tailor therapy in a patient-specific manner. These models can be used to overcome the limited ability of imaging to accurately detect tumor cells, improve prognostic predictions, stratify patients, and assess treatment response in silico in the construction of effective clinical trials and treatment protocols, thus accelerating the pace of clinical research. This presentation will focus on the growing translation of MNO to clinical neuro-oncology highlighting burgeoning insights into sex differences in tumor incidence, outcomes, and response to therapy. Specifically, I will discuss 1) use of our 4,500+ patient cohorts of 100,000+ annotated serial MR imaging data to develop digital twins accurately predict response and outcomes in patients and 2) our unique collection of 1000+ image-localized biopsies across nearly 200 patients to detect sex-distinct patterns of mapping between regional imaging features and underlying regional tumor biology. We will demonstrate the value of these novel combined resources in predicting response to treatment for EGFR-targeted therapies in 3 clinical trials and differentiating response to novel dendritic cells vaccines and CAR T-cell therapies in 2 additional clinical trials. Taken together, these complimentary approaches provide a platform to incorporate inter- and intra- tumoral heterogeneity into accurate predictive models that advance precision oncology for glioblastoma patients. Citation Format: Kristin R. Swanson. Composing each patient’s equation: Unraveling brain tumor complexity by integrating multi-regional image-localized biopsies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY30-03.
Abstract 3938: <i>In vivo</i> genome-wide CRISPR screen in pancreatic ductal adenocarcinoma defines HSPE1 as a potential oncogene by acting through G2/M cell cycle arrest
Authors: Julien Boudreault, Ni Wang, Gang Yan, Meiou Dai, Sophie Poulet, Girija Daliah, Jean-Jacques Lebrun
Journal: Cancer Research (2023)

Abstract Superior knowledge of cancer biology has enabled unprecedented innovations in therapies targeting mutated driver genes. Despite the attempt of targeting cancer-inducing genes such as KRAS, the life expectancy of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) has poorly improved. We performed an unbiased genome wide in-vivo loss-of-function CRISPR screen to discover novel oncogenes and identified heat-shock protein HSPE1, whose function is still unknown in PDAC. By decreasing HSPE1 expression with shRNA and CRISPR technology, we detected a slowdown in cell growth of PDAC cancer cells. HSPE1 knock-out cells injected in mice displayed a drastic reduction in tumor volume. We exploited this vulnerability by disrupting HSPE1 function by using KHS101, a validated HSPD1-HSPE1 complex inhibitor. Several PDAC cell lines cultured in vitro were sensitive upon KHS101 treatment and in vivo administration of KHS101 reduced tumorigenesis. Compiling the negative fitness scores from DepMap database revealed a co-dependency between HSPE1 and PLK1, a protein involved in regulating G2/M checkpoint. Indeed, we detected a protein-level decrease of PLK1 in our experimental model of PDAC cells having either a drug-induced HSPE1 deficiency by KHS101 exposure or a HSPE1 gene-expression reduction by shRNA. We found that the cell cycle was disrupted through G2/M arrest in PDAC cells treated with KHS101. Our findings highlight a new role underlying PDAC tumorigenesis for HSPE1 and could unlock a new area of research towards precision medicine. Citation Format: Julien Boudreault, Ni Wang, Gang Yan, Meiou Dai, Sophie Poulet, Girija Daliah, Jean-Jacques Lebrun. In vivo genome-wide CRISPR screen in pancreatic ductal adenocarcinoma defines HSPE1 as a potential oncogene by acting through G2/M cell cycle arrest. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3938.
Abstract 33: Humanized MOLM-13 AML model as a versatile tool to study immune-activating agents
Authors: Carla Castro, Philipp Metzger, Cynthia Obodozie, Holger Weber
Journal: Cancer Research (2023)

Abstract Acute myeloid leukemia (AML) is the most common acute leukemia and second most common form of blood cancer in children and adolescents. Despite progress in understanding the biology of AML, therapeutic intervention plans have not changed nor outcomes significantly improved over the last years. Current AML treatment consists of intensive chemotherapy followed by stem cell transplantation. While initially many patients respond well to chemotherapy, relapse rates are high and still associated with poor prognosis. Evidence suggests that chemo-resistant leukemic stem cells (LSCs) have the ability to reinitiate and sustain the disease. Therefore, novel therapies are urgently needed to improve AML treatment and well-characterized in vivo models modelling this disease are a prerequisite for improving the current state. At Reaction Biology, we have used NOG and NOD-SCID mice to establish a humanized MOLM-13 AML model concomitantly engrafted with human T cells. Luciferase positive MOLM-13_Luc AML cells were injected both in naïve mice and mice pre-treated with Cyclophosphamide. Thereafter, tumor growth was monitored by bioluminescence measurements to track disseminated tumor burden and isolated T cells were applied upon tumor growth detection (generally observed on day 8 or 15 post-tumor cell inoculation for NOG or NOD-SCID mice, respectively). For each of the inoculations, fresh T cells were obtained by negative selection from buffy coat derived PBMCs with a purity of &amp;gt;95 %. Following administration of human T cells, animals were monitored daily, including the collection of animal weights (3x/w), and tumor burden (2x/w) via in vivo bioluminescence imaging technique. MOLM-13_Luc tumor cells grew rapidly in all NOG mice with termination of the last animals as early as day 17. Neither Cyclophosphamide pre-treatment, nor the addition of T cells influenced tumor growth or prolonged survival. In Cyclophosphamide pre-treated NOD-SCID mice, onset of tumor growth was observed to initiate homogenously at day 13 post inoculation (with applied T cells being ineffective in reducing tumor burden), whereas tumor growth in non-pre-treated animals was heterogenous and delayed by more than 7d. The presence of T cells affected tumor growth even further. Beside T cell addition, also the application of NK cell therapies were successfully investigated (data not shown). Taken together, the MOLM-13_Luc AML tumor model is found to be suitable for the investigation of bi-specific engagers using isolated T or NK cells. Citation Format: Carla Castro, Philipp Metzger, Cynthia Obodozie, Holger Weber. Humanized MOLM-13 AML model as a versatile tool to study immune-activating agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 33.
Abstract 1618: A highly selective and potent TLR8 agonist ZG0895 in preclinical studies of anti-tumor activities
Authors: Dawei Cui, Ruifeng Liu, Huanyi Yang, Bing Zhu, Zelin Sheng, Binhua Lv
Journal: Cancer Research (2023)

Abstract Toll-like receptor 8 (TLR8) recognizes ssRNA fragments from pathogens and initiate both innate and adaptive immune responses. TLR8 activation can reverse Treg and myeloid-derived suppressor cells (MDSC) mediated immune suppression by tumors that lead to a restore of immune response to inhibit tumor growth. ZG0895 is a potent and novel TLR agonist that shows a highly selective activation of TLR8 and has a more than 300-fold potency over TLR7 in EC50 values. The agonist screening results further confirmed that ZG0895 without activation of TLR isoforms like TLR2, 4 or 9 in cells. In pharmacokinetics and pharmacodynamics, ZG0895 has a preferable ADME and PK profile and can activate immune system via subcutaneous (s.c.) administration. For in vivo anti-tumor efficacy studies, ZG0895 at 1~30 mg/kg exhibited significant dose-dependent inhibition of tumor growth in immunocompetent myeloid-sufficient murine models with CT26, EMT6 or HH subcutaneous xenografts. Furthermore, ZG0895 administration resulted in a complete tumor regression by ZG0895 at high dose via s.c. injection. Mechanism studies of ZG0895 in ex vivo human PBMC assay showed a strong induction of TLR8 related cytokines. In vivo study in tumor-bearing mouse demonstrated that pro-inflammatory cytokines, such as TNFα, IL12p40, IL6 and IL10, were quickly released after ZG0895 treatment but soon returned to normal that can avoid continuous activation of systemic immunity and reduce the risk of cytokine release storm. Consistently, in vivo cynomolgus monkey study by consecutive treatments with ZG0895 (day 30) resulted in a significant increase of immune system cells including intermediate monocytes, non-classic monocytes, cDCs and NK cells, along with notable decrease of classical monocytes but unchanged pDCs, suggesting a possible reversion of tumor-initiated MDSC via TLR8 activation. All these changes were back to normal after period of recovery (day 57), indicated the immune effect of ZG0895 was restrained. These preclinical results support that ZG0895 as a highly TLR8-selective agonist inhibits tumor growth via the activation of TLR8 eliciting immune responses but under a better safety than other conventional TLR8 agonists, and it is worth to be further explored as an anti-cancer drug candidate. Citation Format: Dawei Cui, Ruifeng Liu, Huanyi Yang, Bing Zhu, Zelin Sheng, Binhua Lv. A highly selective and potent TLR8 agonist ZG0895 in preclinical studies of anti-tumor activities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1618.
Abstract 6022: The importance of DNA methylation to breast cancer cell phenotype and its role in the anticancer activity of withaferin-A
Authors: Andrew Brane, Trygve O. Tollefsbol
Journal: Cancer Research (2023)

Abstract Breast Cancer (BC) is a widespread malignancy that affects the lives of millions of women each year. Prevention of BC through administration of epigenetically active dietary phytochemicals has received increased interest in recent years due to its relatively low cost, few side effects and potential to reduce the financial and healthcare burdens associated with BC. Many phytochemicals’ anticancer functions are thought to arise from their effects on the epigenome, although the relative importance of specific genes’ epigenetic states remain unclear. To elucidate this, we utilized human BC cell lines in combination with CRISPR-dCas technology tied to methylation modifiers to explore the importance of gene specific DNA methylation to cancer cell phenotype in both naïve BC cells and BC cells treated with the phytochemical Withaferin A (WA). We found that demethylation of promoters of the tumor suppressors p21 and p53 results in increased gene expression, while methylation of the promoter of the oncogene CCND1 results in decreased in gene expression. Additionally, changes to biological processes were associated with tumor suppressor promoter methylation state, including increases in cell cycle arrest for a demethylated p21 promoter and decreases in cell viability for a demethylated p53 promoter. We also found that downregulation of p21 through targeting DNMT3A to its promoter was able to ablate the anticancer function of WA in both MDA-MB-231 and MCF-7 cells. Taken together, these results highlight the potential importance of DNA methylation changes for cancer cell phenotype and a possible mechanism of action for the phytochemical WA in BC prevention. Citation Format: Andrew Brane, Trygve O. Tollefsbol. The importance of DNA methylation to breast cancer cell phenotype and its role in the anticancer activity of withaferin-A [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6022.
Abstract 4387: Total toxicity burden of FDA approved immune checkpoint inhibitors in USA
Authors: Fan Yang, Chloe Shay, Zhaohui Qin, Nabil Saba, Yong Teng
Journal: Cancer Research (2023)

Abstract Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for multiple cancers, demonstrating effective and durable responses and becoming the standard of care for a variety of malignancies. However, ICI-based treatment has resulted in the rise of unique immune-related adverse events (irAEs). To date, very little information is available on the frequency, significance, and management of single-organ or multiorgan irAEs in clinic. In this study, the irAEs associated with the treatment of seven FDA-approved ICIs, including three PD-1 inhibitors (cemiplimab, nivolumab and pembrolizumab), three PD-L1 inhibitors (atezolizumab, avelumab and durvalumab), and one CTLA4 inhibitor (ipilimumab), were analyzed based on the data of 149,303 report cases (January 1, 2015 - June 30, 2022) collected from FDA Adverse Events Reporting System (FAERS) public dashboard. Our data reveal that irAEs associated with the treatment of anti-PD-1 ICIs (e.g., pembrolizumab) require less hospital care resources compared with anti-PD-L1 and anti-CTLA4 ICIs. Tissue and organ toxicity of ICIs are age and gender specific. ‘Cardiac disorders’ is the main disorder caused by these ICIs in cancer patients aged 65-85, while ‘reproductive system and breast disease’ is the main disorder in cancer patients aged 18-64. There are risks of respiratory and urinary system toxicity in male patients and reproductive system toxicity in female patients when they receive the treatment of ICIs. Studies such as this one provide the statistical data for understanding patients at risk of developing irAEs, which will underscore the importance of further exploring research strategies to predict, detect, and mitigate toxicities from ICIs. Citation Format: Fan Yang, Chloe Shay, Zhaohui Qin, Nabil Saba, Yong Teng. Total toxicity burden of FDA approved immune checkpoint inhibitors in USA. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4387.
Abstract 3902: Glutathione as a potential marker of tamoxifen resistance in breast cancer
Authors: Yazan I. Hamadneh, Mohammad AlWahsh, Jawad Alrawabdeh, Roland Hergenröder, Lina A. Dahabiyeh, Lama Hamadneh
Journal: Cancer Research (2023)

Abstract Glutathione (GSH) is an antioxidant with an important protective intracellular role against reactive oxygen species. Increased glutathione level is associated with higher rates of metastases and a more aggressive behavior in breast cancer. This study aims to study the molecular and metabolic changes in glutathione synthesis in tamoxifen resistant (TAM-R) MCF-7 breast cancer cell lines.Methods: Three tamoxifen resistant MCF-7 cell lines were produced by using two methods. The first was achieved by treating the cells with tamoxifen and gradually increasing the amount until reaching a predetermined concentration of tamoxifen. The second was achieved by giving multiple fixed concentrations of tamoxifen, the third model was produced from the second by treating the cells with continuous 1µM of tamoxifen. mRNA and metabolites were extracted from the cell lines. cDNA was synthesized from the extracted mRNA, and gene expression of glutathione synthetase (GSS) was measured using real-time PCR. Nuclear Magnetic Resonance technique with PABO probe was used for metabolic profiling of extracted metabolites from the resistant and sensitive MCF-7cells and Chenomix software for quantification. Additionally, Kaplan Meier plotter (https://kmplot.com/) was used to predict the significance of GSS gene expression to overall survival of breast cancer patients. Results: A significant increase in glutathione accompanied with significant decrease in cysteine levels were found in TAM-R cells compared to control TAM sensitive cells. However, there was a 2 times reduction in the expression of GSS in TAM-R cells. Correlation of GSS gene expression among ER +ve, PR +ve patients who received tamoxifen in their therapy showed that its down regulation is significantly linked to poor overall survival (p-value 0.022 and HR of 0.7). Conclusion: The significant increase of glutathione in TAM-R cells may contribute to their increased resistance to oxidative stress and exhibition of a more aggressive behavior. Moreover, the decrease in GSS expression is a strong indicator of decreased glutathione synthesis in TAM-R cells as a result of cysteine depletion in the cells that was correlated to poor overall survival among BC patients. However, high glutathione levels in TAM-R cells could be due to increased glutathione regeneration in TAM-R cell lines compared to control. Citation Format: Yazan I. Hamadneh, Mohammad AlWahsh, Jawad Alrawabdeh, Roland Hergenröder, Lina A. Dahabiyeh, Lama Hamadneh. Glutathione as a potential marker of tamoxifen resistance in breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3902.
Abstract 1180: Identification of target proteins for breast cancer genetic risk loci and blood risk biomarkers in a large study by integrating genomic and proteomic data
Authors: Guochong Jia, Yaohua Yang, Jie Ping, Shuai Xu, Lili Liu, Xingyi Guo, Ran Tao, Jirong Long, Wei Zheng
Journal: Cancer Research (2023)

Abstract Genome-wide association studies (GWAS) have identified around 200 loci associated with breast cancer risk. However, protein targets for these loci remain largely unknown. Identifying protein targets and biomarkers can improve the understanding of cancer biology and etiology and identify high-risk individuals for cancer prevention. In this study, we investigated genetically predicted levels of 1,142 circulating proteins with breast cancer risk in 133,384 cases and 113,789 controls of European ancestry included in the Breast Cancer Association Consortium (BCAC). We identified 22 blood protein biomarkers associated with the risk of overall breast cancer at a false discovery rate (FDR) &amp;lt;0.05, including nine proteins encoded by genes located at least 500kb away from previously reported risk variants for breast cancer. Analyses focusing on 124 encoding genes located at GWAS-identified breast cancer risk loci found 20 proteins associated with overall breast cancer risk and one protein associated with triple-negative breast cancer risk at FDR &amp;lt;0.05. Adjustment for the GWAS-identified risk variants significantly attenuated the association for 13 of these proteins, suggesting that these proteins may be the targets of these GWAS-identified risk loci. The identified proteins are involved in various biological processes, including glutathione conjugation, STAT5 signaling, and NF-kB signaling pathways. Our study identified novel protein targets and risk biomarkers for breast cancer risk. Citation Format: Guochong Jia, Yaohua Yang, Jie Ping, Shuai Xu, Lili Liu, Xingyi Guo, Ran Tao, Jirong Long, Wei Zheng. Identification of target proteins for breast cancer genetic risk loci and blood risk biomarkers in a large study by integrating genomic and proteomic data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1180.
Abstract 4814: Compensatory interplay of p97 segregase and HSP70 chaperone protect cancer cells from heat-induced proteotoxicity
Authors: Zdenek Skrott, Katarina Chroma, Petr Muller, Ales Panacek, Jiri Bartek, Martin Mistrik
Journal: Cancer Research (2023)

Abstract Due to malignant transformation, cancer cells are characterized by elevated levels of genotoxic, replication or proteotoxic stresses, which makes them vulnerable to various external conditions, including increased temperature. Thus, hyperthermia represents a very effective therapeutic modality usually combined with standard chemotherapy or radiation. Moreover, the elevated temperature is often used in experimental studies related to protein aggregation, cellular heat shock response and other proteostasis mechanisms relevant to cancer progression and treatment. Recently, we developed a single-cell method to inflict defined, subcellular thermal damage, adopting the plasmon resonance principle. Dose-defined heat causes protein damage in subcellular compartments, rapid heat-shock chaperone recruitment, and ensuing engagement of the ubiquitin-proteasome system, providing unprecedented insights into spatiotemporal response to protein damage relevant to cancer. Using this versatile method, we discovered so-far unsuspected compensatory interplay of p97 translocase, the ubiquitin-proteasome system and heat shock protein chaperones in the processing of heat-damaged proteins. As both, p97 and heat shock proteins, represent potential cancer-relevant drug targets, these results can contribute to the development and better implementation of related therapies in cancer treatment. Citation Format: Zdenek Skrott, Katarina Chroma, Petr Muller, Ales Panacek, Jiri Bartek, Martin Mistrik. Compensatory interplay of p97 segregase and HSP70 chaperone protect cancer cells from heat-induced proteotoxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4814.